title: A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma.
abstract: Congenital (or infantile) fibrosarcoma (CFS) is a malignant tumour of fibroblasts that occurs in patients aged two years or younger. CFS is unique among human sarcomas in that it has an excellent prognosis and very low metastatic rate. CFS is histologically identical to adult-type fibrosarcoma (ATFS); however, ATFS is an aggressive malignancy of adults and older children that has a poor prognosis. We report a novel recurrent t(12;15)(p13;q25) rearrangement in CFS that may underlie the distinctive biological properties of this tumour. By cloning the chromosome breakpoints, we show that the rearrangement fuses the ETV6 (also known as TEL) gene from 12p13 with the 15q25 NTRK3 neurotrophin-3 receptor gene (also known as TRKC). Analysis of mRNA revealed the expression of ETV6-NTRK3 chimaeric transcripts in all three CFS tumours analysed. These were not detected in ATFS or infantile fibromatosis (IFB), a histologically similar but benign fibroblastic proliferation occurring in the same age-group as CFS. ETV6-NTRK3 fusion transcripts encode the helix-loop-helix (HLH) protein dimerization domain of ETV6 fused to the protein tyrosine kinase (PTK) domain of NTRK3. Our studies indicate that a chimaeric PTK is expressed in CFS and this may contribute to oncogenesis by dysregulation of NTRK3 signal transduction pathways. Moreover, ETV6-NTRK3 gene fusions provide a potential diagnostic marker for CFS.
authors.affiliation: Department of Pathology, British Columbia's Children's Hospital, Vancouver, Canada.
authors.forename: S R
authors.initials: SR
authors.lastname: Knezevich
authors.forename: D E
authors.initials: DE
authors.lastname: McFadden
authors.forename: W
authors.initials: W
authors.lastname: Tao
authors.forename: J F
authors.initials: JF
authors.lastname: Lim
authors.forename: P H
authors.initials: PH
authors.lastname: Sorensen
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D019677:Artificial Gene Fusion; D001483:Base Sequence; D002648:Child; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D002884:Chromosomes, Human, Pair 15; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D005354:Fibrosarcoma / Q000151:congenital / Q000235:genetics*; D005819:Genetic Markers; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D007231:Infant, Newborn; D007621:Karyotyping; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D050783:Proto-Oncogene Proteins c-ets; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000737:chemistry / Q000235:genetics*; D012097:Repressor Proteins; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*; D014178:Translocation, Genetic; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D004268:DNA-Binding Proteins; D005819:Genetic Markers; D009687:Nuclear Proteins; D050783:Proto-Oncogene Proteins c-ets; D020794:Receptor Protein-Tyrosine Kinases; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor; D012097:Repressor Proteins; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein